REVIEW Open Access

What is the impact of n-3 PUFAs oninflammation markers in Type 2 diabeticmellitus populations?: a systematic reviewand meta-analysis of randomizedcontrolled trialsNing Lin1*, Jiao-jiao Shi1, Yun-Ming Li2, Xin-Yan Zhang2, Yi Chen1, Philip C. Calder3,4 and Li-Jun Tang5

Abstract

Objectives: To explore the possible role of n-3 polyunsaturated fatty acids (PUFAs) in lowering inflammationmarkers in individuals with type 2 diabetes mellitus.

Methods: PubMed, CNKI and Cochrane databases were searched until December 30, 2015; references from papersor reviews were also retrieved and screened. Screening was performed by two independent researchers, andrandomized controlled trials reporting the specific n-3 PUFA type, dose, frequency, and duration of treatment, aswell as the baseline and follow-up concentrations of inflammation markers, including interleukin 2 (IL-2), interleukin6 (IL-6), tumor necrosis factor alpha (TNF-α) and C-reactive protein (CRP), were selected for final analysis. Dataanalysis was performed using RevMan 5.2 software.

Results: Eight studies involving 955 participants were included; all reported CRP. Only one included study reportedIL-2 or IL-6 while two studies reported TNF-α. N-3 PUFAs significantly reduced CRP concentration compared withcontrol [SMD 95 % CI, 1.90 (0.64, 3.16), Z = 2.96, P = 0.003, random effect model].

Conclusions: N-3 PUFAs decrease CRP concentration in type-2 diabetes mellitus. However, larger and rigorouslydesigned RCTs are required to confirm this finding and extend it into other inflammatory biomarkers.

Keywords: N-3 PUFAs, Inflammation markers, Type 2 diabetes mellitus, Fish oil

BackgroundDiabetes is a major global health concern with an in-creasing prevalence. It is estimated that by 2030, ap-proximately 366 million adults will be diagnosed withdiabetes worldwide [1]. There is a considerable healthexpenditure on the control of diabetes and the preven-tion of its comorbidities. Both type 1 and type 2 diabetesare associated with increased blood concentrations ofseveral inflammatory biomarkers, including C-reactiveprotein (CRP), interleukin (IL)-2, IL-6 and tumour ne-crosis factor-alpha (TNF-α) [2–4]. Such low-grade

inflammation, which may possibly be beneficial in theearly stage for promoting β-cell proliferation and insulinproduction to compensate for insulin resistance, is themechanism underlying insulin resistance [5].Although they are strongly linked to chronic low-

grade inflammation, diseases such as atherosclerosis,type 2 diabetes mellitus (T2DM) and obesity are notusually treated with anti-inflammatory pharmaceuticals.However, it is thought that many dietary factors can in-fluence various aspects of inflammation either promot-ing or retarding specific inflammatory components [6].Thus, nutrition may play a role in predisposing individ-uals to conditions that have an inflammatory compo-nent, and altered nutrition may be useful in preventingor treating such conditions.

* Correspondence: helenmedic@yeah.net1Department of Clinical Nutrition, Chengdu Military General Hospital,Chengdu 610083, ChinaFull list of author information is available at the end of the article

© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Lin et al. Lipids in Health and Disease (2016) 15:133 DOI 10.1186/s12944-016-0303-7

Omega-3 (n-3) fatty acids are a family of polyunsatur-ated fatty acids (PUFAs) that are characterized by theposition of a double bond in the hydrocarbon (acyl)chain being between carbon numbers 3 and 4 countingthe terminal methyl carbon as number one. Longerchain n-3 fatty acids include eicosapentaenoic acid (EPA;20:5n-3), docosapentaenoic acid (DPA; 22:5n-3) and doc-osahexaenoic acid (DHA; 22:6n-3) [7]. Epidemiological,human intervention, animal and cell culture studies haveprovided evidence supporting a beneficial role for dietaryn-3 PUFAs in many conditions associated with low-grade chronic inflammation [6, 8–10]. N-3 PUFAs canpotentially decrease inflammation through several mech-anisms, including inhibition of the arachidonic acid(AA) pathway, inhibition of nuclear factor kappa B acti-vation, and initiation of anti-inflammatory signallingthrough G-protein coupled receptor 120 [11–13].Whether n-3 PUFAs favorably affect biomarkers of in-

flammation in people with T2DM is not clear. Our aimwas to perform a systematic review and meta-analysis toinvestigate whether n-3 PUFAs affect inflammationmarkers in T2DM.

Materials and methodsLiterature searchAll English and Chinese language literature publishedbefore December 30, 2015, was retrieved from PubMed,China National Knowledge Infrastructure (CNKI), andCochrane library databases, and RCTs involving n-3PUFAs and patients with T2DM were independentlyscreened for by two researchers. The following searchstrategy was used:

# 1 ((“fatty acids”[MeSH Terms] OR (“fatty”[All Fields]AND “acids”[All Fields]) OR “fatty acids”[All Fields]))# 2 n3 [All Fields] AND #1# 3 (“fatty acids, omega-3” [MeSH Terms] OR (“fatty”[All Fields] AND “acids” [All Fields] AND “omega-3”[All Fields]) OR “omega-3 fatty acids” [All Fields] OR“omega 3 fatty acids” [All Fields])),# 4 (“fish oils” [MeSH Terms] OR (“fish” [All Fields]AND “oils” [All Fields]) OR “fish oils” [All Fields] OR(“fish” [All Fields] AND “oil” [All Fields]) OR “fish oil”[All Fields]),# 5 “#2” OR “# 3” OR “# 4”,# 6 (“inflammation” [MeSH Terms] OR “inflammation”[All Fields]),# 7 Clinical Trial [ptyp],# 8 “#5” AND “# 6” AND “# 7”.

Titles and abstracts were obtained for selected articles.Citation indices and reference lists of retrieved articleswere checked for additional studies that were not identi-fied in the original database search.

Study selectionIn phase 1, all papers retrieved by an independentauthor were reviewed by at least two other authors whoindependently selected the papers that they believed metthe inclusion criteria for full-text reading. In cases ofdisagreement, the researchers discussed their differentassessments and reached a consensus. In phase 2, thefirst author reviewed all full articles that met the eligibilitycriteria. The following inclusion criteria were applied:

� a study should report the baseline and after-treatment data for at least one inflammationbiomarker;

� all study subjects should be diagnosed or confirmedwith T2DM, with reported impaired fasting glucose;

� a control arm, with or without a placebo, should bedescribed.

After confirming the included literature, baseline andpost-treatment inflammation biomarker data wereselected and placed in a PICOS table that included theauthor names, publication year, participant characteristics,intervention and controlled arms, and n-3 PUFA dose, aswell as the control, baseline and end-point levels of eachreported inflammation biomarker.

Data collection and calculationIf the required data could not be directly gathered fromthe paper, the corresponding author was contacted byemail to request these details. The Δ change value of anyinflammation marker equals the after-treatment valueminus the baseline value. Finally, the Δ change of the in-flammation markers in the n-3 PUFA and control armswere compared. If the Δ change value was reported inthe paper or as supplementary material, the data weredirectly used for the analysis.If a study reported inflammation markers at two or

more time points, for example at 12 and 16 weeks ofintervention, we regarded them as two subgroups.

Quality evaluationClinical trial bias and the quality of the literature wereevaluated by two independent researchers, according tothe Cochrane risk of bias guidelines [14], which includedrandom sequence generation, allocation concealment,blinding of participants, personnel and outcome assessors,incomplete outcome data, selective outcome reporting,and other bias measurements (Additional file 2).

Statistical analysisFor continuous variables, the pooled effect was reportedas the standardized mean difference (SMD), with thecorresponding 95 % CI [15]. Heterogeneity was assessedusing I2 tests, and a p value of < 0.05 was considered to

Lin et al. Lipids in Health and Disease (2016) 15:133 Page 2 of 8

be significant. If heterogeneity was present, the pooledeffect size was calculated through a random-effectsmodel.

ResultsSearch results and study characteristicsWe identified 3312 published papers from three data-bases (Fig. 1). Review articles, viewpoints, editorials,commentaries, and animal studies were excluded. Clin-ical trials that did not provide data on the effect of n-3PUFAs on any of the evaluated inflammation markerswere also excluded. According to the inclusion and ex-clusion criteria, 8 RCTs [16–23] were selected for inclu-sion (Fig. 1, Additional files 1 and 2). Reference papersidentified in other reviews of n-3 PUFAs and T2DMwere also retrieved, but none were included in the finalanalysis. In total, data from 8 RCTs in T2DM were in-cluded in the analysis.

Effect of N-3 PUFAs on inflammation markersEight RCTs were selected for the final analysis; these in-cluded 955 participants (Table 1). In all eight studies theage of all participants was over 18 y. The duration of n-3PUFA intervention ranged from 6 to 12 weeks. Eitherfish oil providing a mix of EPA and DHA or pure EPAor DHA were used and in all studies these were pro-vided in capsules. The minimum daily dose of n-3PUFAs used was 1 g and the maximum was 6 g (Table 1).Data for inflammation biomarkers from the eight in-cluded studies are shown in Table 2.A pooled analysis of the 8 included studies [16–23] en-

rolling 955 T2DM subjects revealed that the concentra-tion of CRP was significantly decreased in the n-3 PUFAgroup compared with the control group (SMD 1.90;95 % CI, 0.64 to 3.16, p = 0.003; Fig. 2. The test for het-erogeneity was significant (I2 = 98 %, p < 0.00001).

For a subgroup analysis, EPA and DHA were testedseparately (Fig. 3). Although the heterogeneity was sig-nificant in both subgroups, the P values for the SMD ineach analysis were less than 0.05 indicating that bothEPA and DHA lower CRP concentration.Only two trials reported data for TNF-α concentration.

Malekshahi Moghadam [17] found that n-3 PUFA intakeat 2.7 g/d significantly lowered TNF-α concentrationcompared to sunflower oil as placebo. However, Mori[19] reported that neither EPA nor DHA at 4 g/d low-ered TNF-α concentration in early-stage T2DM patients.Only one trial explored the effects of n-3 PUFAs on

IL-2 and IL-6 in T2DM [18, 19]. IL-2 concentration wassignificantly decreased in T2DM subjects who under-went an 8-week intervention with 2.7 g/d n-3 PUFAs.No significant effect of n-3 PUFAs on IL-6 concentra-tion was detected.

DiscussionThe overall findings from this systematic review andmeta-analysis suggest that supplemental n-3 PUFAs canlower CRP concentration in patients with T2DM, al-though the heterogeneity was significant among the se-lected studies. There were too few studies to evaluatethe effect of n-3 PUFAs on other inflammatory bio-markers in T2DM to reach any clear conclusion.CRP, along with IL-2, IL-6 and TNF-α, belongs to the

cluster of general inflammation markers identified in alarge variety of diseases and conditions. Clinically, CRPhas emerged as a leading inflammatory biomarker forCVD [24] and, thus, has been of interest to researchersstudying the role of n-3 PUFAs in diabetes complica-tions, a key CVD risk factor. Epidemiological studieshave assessed the relationship between CRP concentra-tion and n-3 fatty acid intakes in healthy subjects and inpatients with coronary disease [24, 25], confirming aninverse association and suggesting an anti-inflammatory

Fig. 1 Flow chart for selection of included studies

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Table 1 Characteristics of included studies regarding n-3 PUFA from any source and inflammation markers in T2DM

Intervention arm Control arm

Author/year [referencenumber]

Studytype

Type of patient Location ofstudy

Number included/Numbercompleted

Age (y)(Mean ± SD)

Duration(wk)

N-3 PUFA source Dose(g/d)

Placebo Quality

Brinton 2013 [21] RCT T2DM USA 513/501 >18 12 Icosapent ethyl (EPA) 4, 2 placebo A

Azizi-Soleiman 2013 [16] RCT T2DM Iran 60/45 59.4 ± 8.2 12 EPA or DHA 1 Canola oil B

Lee 2014 [17] RCT Early-stage T2DM or MetS USA 80/59 57.9 8 EPA + DHA 6 Corn oil B

Malekshahi Moghadam2012 [18]

RCT T2DM Iran 84/NA 45–85 (mean54.2)

8 EPA + DHA 2.7 Sunfloweroil

B

Mori 2003 [19] RCT Treated-hypertensive T2DM Australia 59/51 61.2 ± 1.2 6 EPA or DHA 4 Olive oil C

Pooya 2008 [20] RCT T2DM Iran 90/81 45–85 (mean54.5)

8 EPA + DHA 2.2 Sunfloweroil

B

Soleimani 2015 [23] RCT T2DM with diabeticnephropathy (DN)

Iran 60/60 45–85 (mean62.6)

12 Flaxseed oil (ALA) 1 placebo B

Wong 2015 [22] RCT T2DM without priorcardiovasular disease

China 97/91 60 ± 9 (Mean60.1)

12 Fish oil (42 % EPA+25 % DHA)

4 Olive oil A

MetS metabolic syndrome, RCT randomized controlled trial, T2DM type 2 diabetes mellitus, NA not given, ALA alpha-linolenic acid

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Table 2 Inflammation biomarkers pre- and post-intervention across included studies

Placebo N-3 PUFA

Inflammation biomarker Author/year n Pre-intervention Post-intervention n Pre-intervention Post-intervention P (vs placebo) Note

CRP (mg/l) Brinton 2013 [21] 165 2.50 ± 2.88 3.10 ± 3.48 165 2.50 ± 2.07 2.10 ± 2.52 NA 4 g/d EPA

165 2.50 ± 2.88 3.10 ± 3.48 171 2.10 ± 2.67 2.70 ± 2.52 NA 2 g/d EPA

Azizi-Soleiman 2013 [16] 17 2.15 ± 2.29 2.42 ± 2.49 14 2.20 ± 2.65 2.73 ± 3.45 NA EPA treatment

17 2.15 ± 2.29 2.42 ± 2.49 14 2.85 ± 3.58 2.18 ± 2.98 NA DHA treatment

Lee 2014 [17] 21 2.36 ± 0.57 3.72 ± 1.00 16 6.08 ± 3.19 3.59 ± 1.03 NA

Malekshahi Moghadam 2012 [18] 42 18.7 ± 16.8 18.2 ± 11.1 42 25.7 ± 27.4 20.4 ± 24.2 >0.05

Mori 2003 [19] 16 2.01 ± 0.57 2.12 ± 0.57 17 2.28 ± 0.55 2.02 ± 0.43 >0.05 EPA treatment

16 2.01 ± 0.57 2.12 ± 0.57 17 3.70 ± 0.61 3.84 ± 0.73 >0.05 DHA treatment

Pooya 2008 [20] 41 3.15 ± 0.36 3.80 ± 0.17 40 2.70 ± 0.02 2.48 ± 0.23 >0.05

Soleimani 2015 [23] 30 2.93 ± 0.45 2.56 ± 0.43 30 2.66 ± 0.51 2.42 ± 0.45 NA

Wong 2015 [22] 48 1.68 ± 2.53 1.28 ± 1.56 49 1.36 ± 1.43 1.71 ± 3.11 0.15 No adjustment for baseline value

TNF-α (pg/ml) Malekshahi Moghadam 2012 [18] 42 38.7 ± 9.53 40.6 ± 11.0 42 37.5 ± 6.41 34.5 ± 6.40 0.002

Mori 2003 [19] 16 15.35 (10.7–22.0) 14.26 (10.7–18.9) 17 24.44 (18.2–32.9) 19.67 (14.6–26.5) >0.05 EPA treatment

16 15.35 (10.7–22.0) 14.26 (10.7–18.9) 17 20.51 (14.7–28.6) 13.78 (9.50–19.9) >0.05 DHA treatment

IL-2 (pg/ml) Malekshahi Moghadam 2012 [18] 42 42.46 ± 19.78 51.52 ± 19.71 42 42.47 ± 13.85 35.25 ± 11.28 0.0001

IL-6 (pg/ml) Mori 2003 [19] 16 1.76 (1.39–2.23) 1.96 (1.57–2.45) 17 1.75 (1.40–2.20) 1.78 (1.54–2.06) >0.05 EPA treatment

16 1.76 (1.39–2.23) 1.96 (1.57–2.45) 17 2.22 (1.46–3.38) 2.15 (1.52–3.03) >0.05 DHA treatment

Mean ± SD or Geometric mean (95 % confidence interval); For Azizi-Soleiman (2013) we adjusted the reported units for CRP concentration; NA not available

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effect of n-3 PUFAs. EPA and DHA can both decreaseTNF-α levels and improve insulin resistance [26, 27]. InMori’s study, both EPA and DHA tended to decrease theinflammatory marker TNF-α, although this did notreach statistical significance [19]. In vitro and in vivostudies of n-3 and n-6 fatty acids have revealed thatthese fatty acid families could inhibit the production ofinflammatory cytokines, including IL-1, IL-2 and TNF-α,by stimulated human lymphocytes [28]. EPA and DHAwere found to markedly lower IL-2 levels when incu-bated with lymphocytes from diabetic patients or fromcontrols [29].Although several studies support the idea that n-3

PUFAs can potentially lower inflammation markers, thefindings are inconsistent. There are several possible rea-sons for this. First, the type of subjects studied varies

from trial to trial and n-3 PUFAs might be less effectivein some types of subject. For instance, one study foundthat consumption of n-3 PUFAs did not affect theplasma levels of CRP among individuals who suffer fromdyslipidaemia and obesity [30]. In contrast, anotherstudy reported that 4 weeks of n-3 PUFA supplementationlowered serum CRP levels in individuals with inflamma-tory diseases by 93 % [31]. Secondly, dose-dependent ac-tions of n-3 PUFAs on inflammatory responses have notbeen well described, but it appears that a dose of at least2 g/d is necessary to achieve an anti-inflammatory effect[32]. Studies included in the current meta-analysis used avariety of doses, some below the suggested anti-inflammatory threshold. Thirdly, EPA and DHA may havedifferent effects and different studies have used differentmixtures of those two fatty acids. Azizi-Soleiman et al.

Fig. 3 Subgroup analysis of n-3 PUFA on CRP

Fig. 2 Forest plot for effect of n-3 PUFA on CRP concentration in all studies (random effect model)

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showed that 1 g/d of DHA but not EPA was able to lowerCRP concentration [16]. Fourthly, small patient cohorts,short study durations and genetic variability may alsoplay roles in the inconsistencies. An individual’s gen-etic background may affect the response to fish oilsupplementation. In Grimble’s study, SNPs at -308and +252, respectively, of the TNF-α and LT-α geneswere found to influence the ability of fish oil (a source ofn-3 PUFAs) to suppress TNF-α production in a complexmanner [33].In addition, circulating levels of CRP and IL-6 and also

of adiponectin are beneficially modulated by weight lossand (or) exercise [34–36]. Studies of n-3 PUFA supple-mentation tend not to consider body weight, BMI or/and exercise or adjust for these factors as covariates[37].This current study has some limitations. First, the

number of included studies is low, which could give riseto publication bias. Secondly, literature published only inEnglish or Chinese was considered, which may be aselection bias.

ConclusionsIn conclusion, this meta-analysis indicates that personswith T2DM who received n-3 PUFA supplements hadsignificantly lower CRP levels compared with subjects incontrol groups. However, the number and scale of theincluded studies were small. Further carefully designedRCTs are required to confirm this finding and extend itinto other inflammatory biomarkers.

Additional files

Additional file 1: PRISMA 2009 Checklist detail. (DOC 65 kb)

Additional file 2: Quality and study bias of selected literature.(DOCX 14 kb)

AcknowledgementsWe thank DSM for grant support. The funders had no role in study design,data collection and analysis, or preparation of the article.

FundingThis research was funded by a DSM Nutrition Grant, 2013. DSM had no rolein the design, conduct, analysis, or interpretation of data or in writing themanuscript.

Availability of data and materialsAll raw data can be found in reference papers [16–23].

Authors’ contributionsStudy design and conception, NL; literature research, XZ; quality evaluation,NL and JS; data analysis or interpretation, NL, YL, JS, and YC; manuscriptdraft: NL, YL, PCC and LT; and manuscript approval, all authors.

Competing interestsThe authors declare that they have no competing interests.

Consent for publicationThis is a meta-analysis of published data; all source studies have their ownconsent forms for participants and publication. We therefore regard all theparticipants as having agreed this publication.

Ethics approval and consent to participateThis study protocol was approved by the Research Care and EthicsCommittee at the Chengdu Military General Hospital. The protocol numberwas SCCT2012–033.

Author details1Department of Clinical Nutrition, Chengdu Military General Hospital,Chengdu 610083, China. 2Department of Informatics, Chengdu MilitaryGeneral Hospital, Chengdu 610083, China. 3Faculty of Medicine, University ofSouthampton, Southampton SO16 6YD, UK. 4NIHR Southampton BiomedicalResearch Centre, Southampton University Hospital NHS Foundation Trustand University of Southampton, Southampton SO16 6YD, UK. 5Departmentof General Surgery, Chengdu Military General Hospital, Chengdu 610083,China.

Received: 12 July 2016 Accepted: 9 August 2016

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Lin et al. Lipids in Health and Disease (2016) 15:133 Page 8 of 8